The long-term goal of this research program is to understand how eukaryotic DNA replication is regulated during the cell cycle. This problem is central to understanding the mechanisms that control cellular proliferation and maintain genomic stability. Our approach to this problem involves the use of genetic and biochemical methods to identify and characterize genes that couple the basic cell cycle engine to the initiation of DNA replication in the model organism Schizosaccharomyces pombe. We have focused on the cdc18+ gene, which appears to play a central role in the replication switch that triggers initiation once each cell cycle. Our major objectives are to define the role(s) of Cdc 18p in the initiation reaction, to characterize the mechanisms that regulate Cdc 18p activity during the cell cycle, and to analyze the functional interactions of Cdc 18p with other proteins involved in regulating DNA replication, such as SpORC and Cdtlp. We expect that information obtained in our studies will complement that obtained from the study of the Saccharomyces cerevisiae and will be directly relevant to the control of DNA replication in higher eukaryotes.